Non-small cell lung cancer (NSCLC) comprises over 80% of all lung cancer cases. More than two-thirds of NSCLC are diagnosed at a late stage, when current treatments are largely ineffective and only benefit a small portion of patients. Clinical variables alone cannot satisfactorily predict patients' outcomes. Biomarkers are urgently needed to assist in the patient stratification for personalized cancer therapy. Novel therapeutic agents are also highly desired to give patients alternative options after improved prediction of outcomes of treatments. The goals of this project are to identify germline genetic and circulating biomarkers related to microRNA (miRNA) as predictors of survival in late stage NSCLC patients. MiRNAs can regulate up to a third of human genes and play important roles in human carcinogenesis. The inherited genetic variants, mostly in the form of single nucleotide polymorphisms (SNPs), particularly SNPs in miRNA regulatory pathways (miR-SNPs), can also affect expression and/or function of their host and target genes. We propose to conduct a systematic study of miR-SNPs and circulating miRNAs in lung cancer. This proposal builds upon a lung cancer population at MD Anderson Cancer Center, with comprehensive epidemiological and clinical data and rich bio specimens. There are three specific aims: 1) to identify novel germline genetic loci in miR-SNPs that predict survival in patients with late-stage NSCLC. We will use a discovery and validation design with each phase consisting of 1,200 patients for platinum-treated patients; 2) to identify circulating miRNAs as predictors of survival in late- stage NSCLC patients using a testing and a validation set with a total of 800 plasma samples; and 3) to determine the potential disease-causative structural context, biological function, and molecular mechanism of the identified epigenetic miR-SNP and circulating miRNA biomarkers. This is a significant and innovative project incorporating epidemiology, inherited genetics, circulating biomarkers, biological and mechanistic studies, and preclinical therapeutic development.